嘧啶连接的苯并噻唑的抗惊厥潜力的硅内研究、设计和合成。

Amol Kale, Rajendra Kakde, Smita Pawar, Rutuja Thombare, Dhanashree Zope, Ishwar Kakde
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引用次数: 0

摘要

背景:本研究的目的是设计和合成一系列 N-(6-取代-1,3-苯并噻唑-2-基)-2-{[6-(3-取代苯基)-5-氰基-2-硫基嘧啶-4-基)]氨基}乙酰胺衍生物 BPD (1-15),该衍生物含有抗惊厥作用所需的关键药效团:方法:在碳酸钾和干丙酮存在下,通过 2-取代-N-(6-氯苯并[d]噻唑2-基)乙酰胺与 4-氨基-6-(4-取代苯基)-2-巯基嘧啶 5-甲腈反应合成了标题化合物(BPD 1-15)。通过对小鼠进行最大电击(MES)试验和皮下注射戊四唑(scPTZ)试验,对合成的化合物 BPD(1-15)进行了体内评估。神经毒性试验是通过旋转体试验进行的。利用 Maestro 的 Glide 模块中的 SP Docking 协议,对标题化合物与钠通道受体(PDB ID:1BYY)进行了分子对接研究。药理模型用于定性鉴定配体结合的化学特征及其在活性位点三维空间中的空间构型:结果:在所研究的化合物中,BPD-15 和 BPD-5 化合物在 MES 和 scPTZ 模型中均表现出显著作用,且无神经毒性。BPD-15 和 BPD-5 在急性毒性测试中相对安全。BPD-15和BPD-5化合物显示出良好的对接得分,分别为-6.434和-6.191:因此,与标准药物利鲁唑相比,化合物 BPD-15 和 BPD-5 对钠通道具有相当大的亲和力。化合物 BPD-14 显示出良好的药物相容性,化合物 BPD-1、BPD-2、BPD-11、BPD-12、BPD-13、BPD-14 和 BPD-15 显示出良好的 ADME 值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In-silico Studies, Design, and Synthesis of Pyrimidine-linked Benzothiazoles for its Anticonvulsant Potential.

Background: The objective of the study was to design and synthesize a series of N-(6-substituted-1,3-benzothiazole- 2-yl)-2-{[6-(3-substitutedphenyl)-5-cyano-2-sulfanylpyrimidine-4-yl)]amino}acetamide derivatives BPD (1-15) that contains key pharmacophores required for anticonvulsant action.

Methods: The titled compounds (BPD 1-15) were synthesized by reacting 2-substituted-N-(6-chlorobenzo[d]thiazol2-yl)acetamide with 4-amino-6-(4-substituted phenyl)-2-mercapto pyrimidine 5-carbonitrile in the presence of potassium carbonate and dry acetone. The synthesized compounds BPD (1-15) were assessed in vivo by the maximum electric shock (MES) test and the subcutaneous pentylenetetrazol (scPTZ) test in mice. The neurotoxicity test was performed by the rotarod test. A molecular docking study of title compounds with a sodium channel receptor (PDB ID: 1BYY) was carried out using the SP Docking protocol of the Glide module of the Maestro. Pharmacophore modeling was used to qualitatively identify the chemical characteristics for ligand binding and their spatial configurations in the 3D space of the active site.

Result: Among the studied compounds, BPD-15 and BPD-5 compounds showed significant action in both the MES and scPTZ models, with no neurotoxicity. BPD-15 & BPD-5 were relatively safe in acute toxicity testing. Compounds BPD-15 and BPD-5 showed good dock scores of -6.434 and -6.191, respectively.

Conclusion: Thus, the compounds BPD-15 and BPD-5 have shown a considerable affinity towards the sodium channel as compared to the standard drug Riluzole. Compound BPD-14 showed good drug compatibility, and compounds BPD-1, BPD-2, BPD-11, BPD-12, BPD-13, BPD-14, BPD-15 showed good ADME values.

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